Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier.

Fowler syndrome is a rare autosomal recessive brain vascular disorder caused by mutation in FLVCR2 in humans. The disease occurs during a critical period of brain vascular development, is characterized by glomeruloid vasculopathy and hydrocephalus, and is almost invariably prenatally fatal. Here, we sought to gain insights into the process of brain vascularization and the pathogenesis of Fowler syndrome by inactivating Flvcr2 in mice. We showed that Flvcr2 was necessary for angiogenic sprouting in the brain, but surprisingly dispensable for maintaining the blood-brain barrier. Endothelial cells lacking Flvcr2 had altered expression of angiogenic factors, failed to adopt tip cell properties, and displayed reduced sprouting, leading to vascular malformations similar to those seen in humans with Fowler syndrome. Brain hypovascularization was associated with hypoxia and tissue infarction, ultimately causing hydrocephalus and death of mutant animals. Strikingly, despite severe vascular anomalies and brain tissue infarction, the blood-brain barrier was maintained in Flvcr2 mutant mice. Our Fowler syndrome model therefore defined the pathobiology of this disease and provided new insights into brain angiogenesis by showing uncoupling of vessel morphogenesis and blood-brain barrier formation.

A review of extraaxial developmental venous anomalies of the brain involving dural venous flow or sinuses: persistent embryonic sinuses, sinus pericranii, venous varices or aneurysmal malformations, and enlarged emissary veins.

This paper is a narrative review of extraaxial developmental venous anomalies (eDVAs) of the brain involving dural venous flow or sinuses: persistent embryonic sinuses, sinus pericranii, enlarged emissary veins, and venous varices or aneurysmal malformations. The article highlights the natural history, anatomy, embryology, imaging, clinical implications, and neurosurgical significance of these lesions, which the authors believe represent a continuum, with different entities characterized by distinct embryopathologic features. The indications and surgical management options are discussed for these individual intracranial pathologies with relevant illustrations, and a novel classification is proposed for persistent falcine sinus (PFS). The role of neurointervention and/or microsurgery in specific cases such as sinus pericranii and enlarged emissary veins of the skull is highlighted. A better understanding of the pathophysiology and developmental anatomy of these lesions can reduce treatment morbidity and mortality. Some patients, including those with vein of Galen malformations (VOGMs), can present with the added systemic morbidity of a high-output cardiac failure. Although VOGM is the most studied and classified of the above-mentioned eDVAs, the authors believe that grouping the former with the other venous anomalies/abnormalities listed above would enable the clinician to convey the exact morphophysiological configuration of these lesions, predict their natural history with respect to evolving venous hypertension or stroke, and extrapolate invaluable insights from VOGM treatment to the treatment of other eDVAs. In recent years, many of these symptomatic venous malformations have been treated with endovascular interventions, although these techniques are still being refined. The authors highlight the broad concept of eDVAs and hope that this work will serve as a basis for future studies investigating the role of evolving focal venous hypertension/global intracranial hypertension and possibilities of fetal surgical intervention in these cases.

Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage.

Zika virus (ZIKV) infection of pregnant women can result in fetal brain abnormalities. It has been established that ZIKV disrupts neural progenitor cells (NPCs) and leads to embryonic microcephaly. However, the fate of other cell types in the developing brain and their contributions to ZIKV-associated brain abnormalities remain largely unknown. Using intracerebral inoculation of embryonic mouse brains, we found that ZIKV infection leads to postnatal growth restriction including microcephaly. In addition to cell cycle arrest and apoptosis of NPCs, ZIKV infection causes massive neuronal death and axonal rarefaction, which phenocopy fetal brain abnormalities in humans. Importantly, ZIKV infection leads to abnormal vascular density and diameter in the developing brain, resulting in a leaky blood-brain barrier (BBB). Massive neuronal death and BBB leakage indicate brain damage, which is further supported by extensive microglial activation and astrogliosis in virally infected brains. Global gene analyses reveal dysregulation of genes associated with immune responses in virus-infected brains. Thus, our data suggest that ZIKV triggers a strong immune response and disrupts neurovascular development, resulting in postnatal microcephaly with extensive brain damage.

Embryological Consideration of Dural AVF.

BACKGROUND: The distribution of intracranial dural AVFs (DAVFs) may be affected by the embryological bony structures that consist of membranous bone and endochondral bone. METHODS: We retrospectively analyzed the distribution of the shunt points in 58 consecutive cases of DAVFs. Shunt points were identified with selective digital subtraction angiography, high-resolution cone beam computed tomography (CT), or three-dimensional rotation angiography. All the shunt points were plotted on the map of the skull base in relation to the topography of the endochondral bone and the membranous bone. If the shunt point was localized on the surface of endochondral bone, this was categorized as the endochondral bone group. If it was located on membranous bone, this was categorized as the membranous bone group. If the shunt point was independent from both bony structures, this was categorized as the independent group. FINDINGS: In 55 of 58 cases, shunt points were identified angiographically. Three cases had multiple shunts. There were 33 shunt points (60 %) belonging to endochondral bone. In this group, 16 cases of sigmoid, 11 of carotid cavernous, 3 of petrosal apex, and 3 of sigmoid DAVF were observed. There were 12 shunt points (22 %) localized on membranous bone; in this group, there were nine cases of transverse sinus, two of superior sagittal sinus, and one case of confluence DAVF. There were ten shunt points (18 %) independent from these two bony structures: four cases of olfactory groove, four . of middle fossa, and two of hypoglossal canal DAVF. CONCLUSIONS: There were correlations between the localization of shunt points of DAVFs and the topography of endochondral bone and the membranous bone. The histological difference of endochondral bone and membranous bone at the level of epidural space might cause the formation of DAVFs.

Bilateral Internal Carotid Artery Segmental Agenesis: Embryology, Common Collateral Pathways, Clinical Presentation, and Clinical Importance of a Rare Condition.

BACKGROUND: Bilateral segmental agenesis of the internal carotid artery is a rare congenital anomaly. We present a case of bilateral internal carotid artery segmental agenesis in an asymptomatic 18-year-old man. Embryology, common collateral pathways, clinical presentation, and clinical importance of this condition are discussed. According to our review of the literature, this report is the first to describe bilateral internal carotid artery segmental agenesis in a patient studied with magnetic resonance imaging, computed tomography, Doppler ultrasonography, and digital subtraction angiography. CASE DESCRIPTION: An 18-year-old man presented to our hospital complaining of occasional mild headaches. Neurologic examination was unremarkable. Imaging findings consisted of bilateral segmental agenesis of the internal carotid arteries. CONCLUSION: Bilateral segmental agenesis of internal carotid artery may be completely asymptomatic and harmless, but associated conditions, such as cerebral aneurysms or abnormal collateral circulation, should alert clinicians to the possibilities of subarachnoid hemorrhage or cerebral ischemia.

Embryological Consideration of Dural Arteriovenous Fistulas.

The topographical distribution of dural arteriovenous fistulas (DAVFs) was analyzed based on the embryological anatomy of the dural membrane. Sixty-six consecutive cases of intracranial and spinal DAVFs were analyzed based on the angiography, and each shunt point was identified according to the embryological bony structures. The area of dural membranes was categorized into three different groups: a ventral group located on the endochondral bone (VE group), a dorsal group located on the membranous bone (DM group) and a falco-tentorial group (FT group) located in the falx cerebri, tentorium cerebelli, falx cerebelli, and diaphragm sellae. The FT group was designated when the dural membrane was formed only with the dura propria (meningeal layer of the dura mater) and not from the endosteal dura. Cavernous sinus, sigmoid sinus, and anterior condylar confluence was categorized to VE group, which had a female predominance, more benign clinical presentations, and a lower rate of cortical and spinal venous reflux. Transverse sinus, confluence, and superior sagittal sinus belonged to the DM group. Olfactory groove, falx, tent of the cerebellum, and nerve sleeve of spinal cord were categorized to the FT group, which presented later in life and which had a male predominance, more aggressive clinical presentations, and significant cortical and spinal venous reflux. The DAVFs was associated with the layers of the dural membrane characterized by the two different embryological bony structures. The FT group was formed only with the dura propria as an independent risk factor for aggressive clinical course and hemorrhage of DAVFs.

Cranial dural arteriovenous shunts. Part 1. Anatomy and embryology of the bridging and emissary veins.

We reviewed the anatomy and embryology of the bridging and emissary veins aiming to elucidate aspects related to the cranial dural arteriovenous fistulae. Data from relevant articles on the anatomy and embryology of the bridging and emissary veins were identified using one electronic database, supplemented by data from selected reference texts. Persisting fetal pial-arachnoidal veins correspond to the adult bridging veins. Relevant embryologic descriptions are based on the classic scheme of five divisions of the brain (telencephalon, diencephalon, mesencephalon, metencephalon, myelencephalon). Variation in their exact position and the number of bridging veins is the rule and certain locations, particularly that of the anterior cranial fossa and lower posterior cranial fossa are often neglected in prior descriptions. The distal segment of a bridging vein is part of the dural system and can be primarily involved in cranial dural arteriovenous lesions by constituting the actual site of the shunt. The veins in the lamina cribriformis exhibit a bridging-emissary vein pattern similar to the spinal configuration. The emissary veins connect the dural venous system with the extracranial venous system and are often involved in dural arteriovenous lesions. Cranial dural shunts may develop in three distinct areas of the cranial venous system: the dural sinuses and their interfaces with bridging veins and emissary veins. The exact site of the lesion may dictate the arterial feeders and original venous drainage pattern.

Thrombosed dural sinus malformation in a fetus: a case report.

BACKGROUND AND PURPOSE: A thrombosed dural sinus malformation (DSM) is a rare condition, the clinical features of which have not yet been completely characterized. Here, we describe the clinical course of a patient with a thrombosed DSM and discuss the outcomes in live birth cases from a review of the literature. CASE DESCRIPTION: An ultrasonography examination of a 32-year-old woman at 25 weeks' gestation indicated a fetal posterior fossa mass. The size of the intracranial mass remained constant during the second trimester and was observed to decrease from 33 weeks of gestation. A postnatal diagnosis of thrombosis in the dural sinus was established by magnetic resonance imaging and venography. No brain damage or hydrocephalus was noted. Although the circumference of the infant's head was enlarged at birth, her neurological outcome was normal at 1 year of age. CONCLUSIONS: Although normal cranial circumference is reportedly an essential factor for a favorable prognosis, the patient in this report with a cranial circumference at + 2.0 SD (35.6 cm) had a favorable prognosis. Further studies focused on improving clinical diagnostic accuracy in this rare entity will facilitate appropriate counseling.

Dynamic regulation of the cerebral cavernous malformation pathway controls vascular stability and growth.

Cardiovascular growth must balance stabilizing signals required to maintain endothelial connections and network integrity with destabilizing signals that enable individual endothelial cells to migrate and proliferate. The cerebral cavernous malformation (CCM) signaling pathway utilizes the adaptor protein CCM2 to strengthen endothelial cell junctions and stabilize vessels. Here we identify a CCM2 paralog, CCM2L, that is expressed selectively in endothelial cells during periods of active cardiovascular growth. CCM2L competitively blocks CCM2-mediated stabilizing signals biochemically, in cultured endothelial cells, and in developing mice. Loss of CCM2L reduces endocardial growth factor expression and impairs tumor growth and wound healing. Our studies identify CCM2L as a molecular mechanism by which endothelial cells coordinately regulate vessel stability and growth during cardiovascular development, as well as postnatal vessel growth.

Basilar artery fenestration.

The posterior circulation of the brain constitutes the vertebrobasilar system and its branches, which are responsible for about 30% of the brain's blood supply. The aim of this study was to describe the anomalies of the basilar artery, especially fenestrations. For that purpose, we examined 50 patients with computed tomography (CT) angiography during an 8-month period. In the CT reports of 2 (4%) patients of the 50 analysed, fenestration was found at the proximal basilar trunk. The two fenestrations in our series were not associated with aneurysms. No collateral branches originated from the two limbs of the fenestration. In conclusion, basilar artery fenestrations are a rare finding. The data derived from this study are useful teaching material for anatomists, and for the radiologists and neurosurgeons they are important for diagnostic and intervention procedures such as CT, magnetic resonance imaging, angiography, and surgical and endovascular procedures.

Vasoactive intestinal peptide in neurodevelopmental disorders: therapeutic potential.

Vasoactive intestinal peptide (VIP) mediates important events during the development of the nervous system. VIP can stimulate neuronogenesis as well as differentiation and neurite outgrowth; it can promote the survival of neurons and assist in neuronal repair; it is also anti-inflammatory and can modulate immune responses. In addition, VIP is necessary for the normal growth and development of the early postimplantation mouse embryo during the period when the major embryonic events are neural tube formation, neuronogenesis and expansion of the vascular system. Receptors for VIP appear during early postimplantation embryogenesis in the rodent and exhibit changing localization patterns throughout the development of the brain. During embryogenesis, unregulated VIP may have major and permanent consequences on the formation of the brain and may be a participating factor in disorders of neurodevelopment. VIP has been linked to autism, Down syndrome and fetal alcohol syndrome. This paper will review the role of VIP in neurodevelopment, its known involvement in neurodevelopmental disorders and propose ways in which VIP might be of therapeutic value.

[Pre- and postnatal MRI of the fetus with complex intracranial vascular malformation]. / Prä- und postnatale MRT des Fetus bei komplexer intrakranieller vaskulärer Malformation.

Intracranial vascular malformations (IVM) on the whole occur in neonates very rarely. In such cases of IVM two different kinds can and must be discerned: (1) dural arteriovenous shunts (DAVS) and (2) vein of Galen aneurysmal malformations (VGAM). The latter seem to represent the majority of IVM of newborns. Several classifications are known for both types. Mortality of neonates and babies due to DAVS exceeds the average mortality from DAVS in adults. VGAM and DAVS can be diagnosed by prenatal ultrasonography only when the vessels behind the shunt are vasodilated because of the increasing flow stress. For that reason VGAM and DAVS are generally not recognized before the last trimenon or even postnatally. The prognosis of an IVM is influenced by the shunt capacity and its resulting cardiac stress as well as by the child's age. To plan the mostly interventional therapy, postnatal angiography (DSA) and MRI are employed and to an increasing extent also prenatal MRI examinations. We describe the case of a very complex IVM, the full dimensions of which could only be discerned by using pre- and postnatal MRI supplementary to the ultrasonography. Besides DAVS, flows from the pericallosal arteries as well as from the thalamic branches had to be considered. As a consequence DAVS and in addition VGAM existed in parallel.

Prenatal MR imaging of dural sinus malformation: a case report.

OBJECTIVE: To describe prenatal magnetic resonance imaging (MRI) findings of dural sinus malformation (DSM), a very rare, congenital form of dural arteriovenous shunt (DAVS), typically affecting newborns. METHODS: Ultrasound (US) and MRI were performed at 34 weeks' gestation, and the findings of these examinations were compared with postnatal MRI studies performed at 2 days and 1 month. RESULTS: US showed an anechoic, midline posterior fossa collection with irregular internal echodensities. Color Doppler showed prominent arterial vascularity at the lesion margins. The prenatal MRI showed a large, profoundly hypointense, midline retrocerebellar mass. Postnatal MRI, complemented with magnetic resonance (MR) angiography, showed the lesion to be a giant dural venous pouch fed by multiple mural arteriovenous shunts. Follow-up MRI at 1 month suggested latent venous hypertension and prompted endovascular treatment. CONCLUSION: Prenatal MR imaging is useful to establish the diagnosis, to assess complications such as hydrocephalus and tonsillar prolapse, and to help plan perinatal management, postnatal follow-up, and treatment decision-making.

Serial antenatal sonographic observation of cerebral dural sinus malformation.

Dural sinus malformation is an extremely rare congenital cerebrovascular malformation. We report serial antenatal sonographic findings in two patients with dural sinus malformation. Sonography can reveal dural sinus malformation at 24 weeks' gestation. Correct and early diagnosis may help determine the appropriate place, timing, and mode of delivery, which may result in a better therapeutic course and patient outcome.

Second-trimester diagnosis of intracranial vascular anomalies in a fetus with subdural hemorrhage.

OBJECTIVES: Risk factors for intracranial hemorrhage occurring in prenatal life are imperfectly known. A case of prenatal diagnosis of subdural hemorrhage associated with multiple intracranial vascular aneurysms is described. METHODS: Sonography and magnetic resonance imaging of the fetal head were obtained at 21 weeks' gestation and compared with pathologic findings. RESULTS: Sonography showed a large transonic mass displacing the normal intracranial structures. Magnetic resonance imaging demonstrated the hemorrhagic origin of the mass and showed multiple vascular anomalies. Postmortem examination confirmed the compression of the cerebral hemisphere by a blood collection, probably because of bleeding from one of the multiple vascular aneurysms into the subdural space. CONCLUSION: Magnetic resonance imaging with the use of single-shot ultrafast sequences may be useful not only in the differential diagnosis of fetal intracranial hemorrhage but also in identifying vascular risk factors.

[Fetal brain blood flow velocity monitoring in high risk pregnancies]. / Monitorowanie zylnego mózgowego przeplywu krwi u plodu w ciazy wysokiego ryzyka.

OBJECTIVES: Blood velocity in the fetal vein of Galen and straight sinus is normally even and without fluctuation. Transverse sinus blood velocity pattern shows a characteristic triphasic shape. The aim of this study was to establish whether blood flow velocity pulsations in the Galen vein, straight sinus and transverse sinus velocimetry in high-risk pregnancies are related to an adverse outcome. MATERIALS AND METHODS: The Galen vein, straight sinus and transverse sinus were located by color Doppler ultrasound in 110 pregnancies complicated by pregnancy-induced hypertension and intra-uterine growth retardation with blood velocity recorded by pulsed Doppler. The incidences of blood velocity pulsations in Galen vein and straight sinus as well as peak systolic velocity, lowest diastolic velocity and resistance index (RI) from transverse sinus were correlated to pregnancy outcome, including emergency operative intervention and/or neonatal distress. Umbilical artery and venous and uterine and middle cerebral artery blood velocity was also recorded at the same time. RESULTS: Pulsating blood velocity in the Galen vein and transverse sinus was found in 40 and 10 cases, respectively. Signs of brain sparing in the middle cerebral artery were seen in 23 fetuses. Abnormal values for RI, peak systolic velocity and lowest diastolic velocity from transverse sinus were found in 20.6 and 18 cases, respectively. Galen vein pulsations were highly significantly related to adverse outcome of pregnancy and significantly more frequent in the present study than in the umbilical vein. Parameters studied in straight sinus and transverse sinus showed poor correlation with outcome of pregnancy. CONCLUSIONS: Venous pulsations in the Galen vein are significantly correlated to adverse outcome of high-risk pregnancy. Straight sinus and transverse sinus velocimetry was not associated with perinatal outcome and might not be useful in predicting fetal distress.

Prenatal diagnosis of capillary telangiectasia of the cerebellum--ultrasound and MRI features.

OBJECTIVE: To report three cases of capillary telangiectasia (CT) of the cerebellum revealed as focal cerebellar lesions. METHODS: Ultrasound and magnetic resonance imaging (MRI) were performed in all cases in the prenatal period. Prenatal imaging findings were compared with either post-mortem examination (case 1) or post-natal MRI (cases 2 & 3). RESULTS: A discrepancy between a hyperechoic lesion without any mass effect on sonogram and normal T1 and T2 spin-echo fetal magnetic resonance images was found in all cases. The diagnosis of CT was made on post-mortem examination in case 1. Prenatal ultrasound and magnetic resonance imaging findings were suggestive of the diagnosis in cases 2 and 3. In both cases, the pregnancy was managed conservatively and the diagnosis of CT was documented on post-natal MRI after gadolinium injection. CONCLUSION: The diagnosis of CT of the cerebellum was strongly suggested in these three cases in the prenatal period by the combination of ultrasound and fetal MRI findings. In the vast majority of cases, CT has a benign clinical course and complication with haemorrhage appears to be exceedingly rare. This fact should be taken into account in the prenatal counselling.

Morphogenesis of the branchial vascular sector.

The branchial and dorsal cephalic vascular sectors correspond to the blood vessels contained within evolutionarily recent and ancestral parts of the head, respectively. Recent work demonstrates that neural crest cells (NCCs) provide the pericytes, and connective and smooth muscle cells to the entire branchial sector in an ordered fashion. Initial NCC position is transposed to the vascular distal-to-proximal axis, explaining why circumscribed cephalic vascular anomalies are often associated with reproducible malformations in head tissues derived from the neural crest. Unlike the rest of the central nervous system, the forebrain requires mesenchyme-containing vascular-competent NCCs to survive during embryogenesis and beyond.

Krit1/cerebral cavernous malformation 1 mRNA is preferentially expressed in neurons and epithelial cells in embryo and adult.

Cavernous malformations are capillaro-venous lesions mostly located within the central nervous system (CCM/OMIM#116860) and occasionally within the skin and/or retina. They occur as a sporadic or hereditary condition. Three CCM loci have been mapped, and the sole gene identified so far, CCM1, has been shown to encode KRIT1, a protein of unknown function. In an attempt to get some insight on the relationship between KRIT1 mutations and CCM lesions, we investigated Krit1 mRNA expression during mouse development from E7.5 to E20.5 and in adult tissues, of both mouse and human origin. A ubiquitous Krit1 mRNA expression was detected from E7.5 up to E9.5. Then, it became progressively restricted from E10.5 to E12.5, to become detectable later essentially in the nervous system and various epithelia. Strong labelling was observed in neurons in the brain, cerebellum, spinal cord, retina and dorsal root ganglia. In epithelia, Krit1 mRNA expression was detected in differentiating epidermal, digestive, respiratory, uterine and urinary epithelia. A similar pattern of expression persisted in mouse and man adult nervous system and epithelia. Unexpectedly, in vascular tissues, expression of Krit1 was detected only in large blood vessels of the embryo.